The liver is believed to promote tolerance, which may be beneficial due to its constant exposure to foreign Ags from the portal circulation. Although dendritic cells (DCs) are critical mediators of immune responses, little is known about human liver DCs. We compared freshly purified liver DCs from surgical specimens with autologous blood DCs. Liver and blood DCs were equally immature, but had distinct subset compositions. BDCA-1+ DCs represented the most prevalent liver DC subset, whereas the majority of peripheral blood DCs were CD16+. Upon TLR4 ligation, blood DCs secreted multiple proinflammatory cytokines, whereas liver DCs produced substantial amounts of IL-10. Liver DCs induced less proliferation of allogeneic T cells both in a primary MLR and after restimulation. Similarly, Ag-specific CD4+ T cells were less responsive to restimulation when initially stimulated by autologous liver DCs rather than blood DCs. In addition, liver DCs generated more suppressive CD4+ CD25+FoxP3+ T regulatory cells and IL-4-producing Th2 cells via an IL-10-dependent mechanism. Our findings are critical to understanding hepatic immunity and demonstrate that human liver DCs promote immunologic hyporesponsiveness that may contribute to hepatic tolerance.

Whether a freshly isolated immune cell can be equipped with both natural killing and antigenpresenting cell (APC) function has recently become controversial in mice. We sought to probe the existence of a candidate human cell with these properties by searching for cells in healthy subjects that co-express APC surface molecules and NK cell receptors. We have found that CD3 − CD14 − CD19 − mononuclear cells of human blood, spleen, liver, and lymph nodes contain 2 distinct populations of cells that co-express HLA-DR (DR) and CD56. Circulating CD56 + cells expressing high levels of DR were phenotypically and functionally similar to conventional CD56 − dendritic cells (DC). Furthermore, we demonstrate here that a separate cohort of CD56 + cells that express low levels of DR are NK cells that possess dual function as potent killers endowed with weak APC function.

The liver contains a unique repertoire of immune cells and a particular abundance of NK cells. We have found that CD11c defines a distinct subset of NK cells (NK1.1(+)CD3(-)) in the murine liver whose function was currently unknown. In naïve animals, CD11c(+) liver NK cells displayed an activated phenotype and possessed enhanced effector functions when compared with CD11c(-) liver NK cells. During the innate response to adenovirus infection, CD11c(+) NK cells were the more common IFN-gamma-producing NK cells in the liver, demonstrated enhanced lytic capability, and gained a modest degree of APC function. The mechanism of IFN-gamma production in vivo depended on TLR9 ligation as well as IL-12 and -18. Taken together, our findings demonstrate that CD11c(+) NK cells are a unique subset of NK cells in the murine liver that contribute to the defense against adenoviral hepatitis.

The liver harbors a diversity of cell types that have been reported to stimulate T cells. Although most hepatic dendritic cells are immature, a small population of CD11c high conventional dendritic cells (cDCs) exists that expresses high levels of costimulatory molecules. We sought to determine the relative contribution of cDCs to cross-presentation by the liver. A ntigen-presenting cells (APCs) play a critical role in modulating the hepatic immune response to infection, autoimmunity, and malignancy. Crosspresentation, the process by which APCs internalize antigens from the extracellular environment and present them as MHC class I-bound peptides is essential for generating CD8 ϩ T-cell immunity against antigens synthesized in cells. 1 Unlike spleen CD11c ϩ cells, most CD11c ϩ cells in the liver express low levels of MHC class II and costimulatory molecules. 2 Although liver DCs have been shown to prime CD8 ϩ T cells by cross-presentation, several other hepatic cell types have been shown to possess this function as well. 3,4 Limmer et al. reported that liver sinusoidal endothelial cells (LSECs) loaded with soluble protein stimulated T cell receptor (TCR) transgenic CD8 ϩ T cells. 5 Hepatocytes infected with Plasmodium presented antigen to CD8 ϩ T cells, which then acquired antigen-specific lytic activity and secreted interferon-gamma (IFN-␥). 6 Induction of adaptive immunity against the intracellular pathogen Listeria monocytogenes (LM) is mediated primarily by cross-presentation. 7 Hepatic stellate cells infected with LM elicited antigen-specific CD8 ϩ T cell responses in vitro and when loaded with ovalbumin, mediated protection in vivo against an ovalbumin-expressing strain of LM. 8 Kupffer cells, the resident macrophages of the liver, have been reported to cross-present antigen and also secrete interleukin 10, which has potent immunoregulatory effects on antigen presentation. 9 NPCs also contain neutrophils and B cells, which are known to cross-present antigen in other anatomic locations. 10,11 In the mouse, CD11c high cells have been termed cDCs to distinguish them from plasmacytoid DCs (pDCs), which are CD11c int . 12,13 To determine the relative contribution of hepatic cDCs to cross-presentation of soluble protein in the liver, where there are other cells with APC function, we performed in vitro studies with bulk NPCs devoid of cDCs. Furthermore, we utilized CD11c-diphtheria toxin receptor (CD11c-DTR) transgenic mice, in which cDCs are selectively depleted, to monitor the accumulation of antigen-specific T cells in the liver after antigen exposure. Our results indicated that liver cDCs play a dominant role in effective cross-presentation of soluble antigen and that other hepatic APCs cannot substitute for cDCs in the induction of a maximal effector T-cell response by the liver.Abbreviations: CFSE,5, DC, dendritic cell; DT, diphtheria toxin; Flt3L, LM, Listeria monocytogenes; NPC, nonparenchymal cell.

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